Process for producing delta9,11-12-keto steroids from delta8,9-12-keto steroids



Patented Nov. 11, 1952 Es PATENT OFFICE PROCESS FOR PRODUCING A -12-KETO STEROIDS FROM A d-IZ-KETO STEROIDS Evelyn H. Wilson, East Orange, and Max Tishler, West'field, N. J assignors to Merck & 00., Inc., Rahway, N. 'J., a'corporation of New Jersey No Drawing. Application November 29, 1950,

Serial No. 198,238

. 18 Claims. (Cl. 260-3971) This invention relates to compounds of the cyclopentanopolyhydrophenanthrene series having a 12-keto group and a double bond in the 9.11 position, and more particularly to the preparation of such compounds.

The cyclopentanopolyhydrophenanthrene compounds having a 12-keto group and a double bond in the-9,11 position are useful as intermediates in the preparation of steroid compounds having an ll-keto group. For example, 3-hydroxy-A -12- ketocholenic acid can be utilized as a starting material to prepare S-hydroxy-ll-ketocholanic acid and derivatives thereof which may be further treated to obtain the therapeutically important comp und, Kendalls Compound E (17-hydroxy-ll-dehydrocorticosterone).

It is an object of the present invention to provide an improved process for preparing A -12'- keto cyclopentanopolyhydrophenanthrene compounds. It is a further object to provide a process for converting cyclopentanopolyhydrophenane threne compounds having a l2-keto substituent and a double bond in the 8,9 position to the desired A -12-keto compounds. Another object isto provide an improved method for obtaining 3-hydroxy-A -l2-ketocholenic acid. Other objects of this invention will be apparent from the detailed disclosure hereinafter provided.

In accordance with one embodiment of our invention, we have found that cyclopentanopolyhydrophenanthren'e compounds having a 12-keto substituent and a double bond in the 8,9 position are readily converted to the corresponding A 12-keto compound by reaction with a mineral acid or a strong alkali. This reaction may be illustrated as follows:

The compoundsillustrated above may also contain substituents such as hydroxy, acyloxy, ket o, alkyl, carboxyalkyl, and the like in rings A, B and D. a The reaction is effected by intimately "contacting the A -l2-keto compound with a mineral acid or a strong alkali. Mineral acids suitable.

for this purpose include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. By the term, strong alkalis, as used herein, is meant those alkaline substances which in solution exhibit a pH above 8, such as the alkali metal hydroxides and alkali metal alcoholates (inter alia, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, and the like) After the isomerization is completed, the desired product is conveniently recovered in accordance with conventional methods.

As suitable starting materials in the process of our invention there may be mentioned, A lZ-ketopregnene, 3-hydroxy-At l2 ketopregnene, 3-acy1oxy-A -12-ketopregnene, A -12- ketocholenic acid, 3-hydroxy-A -lz-ketocholenic acid, 3-acyloxy-A -12-ketocholenic acid, A -12- ketoetiocholenic acid, 3-hydroxy-A -12-ketoetiocholenic acid, 3-acyloxy-A lz-ketoetiocholenic acid, esters of such acids, and the like. When the starting compound contains an acyloxy substituent this group is hydrolyzed under the reaction conditions to yield a hydroxy substituent. Also, when esters are treated with strong alkalies, hydrolysis occurs and the free acid derivative is obtained. However, this is immaterial to our invention since, if'desired, the isomerized product may be acylated or 'esterifled in accordance with conventional chemical practice to obtain the desired acylated and/or esterified derivative.

In carrying out the process of our invention we have achieved maximum yields of the desired product under optimum conditions by reacting the A -12-keto cyclopentanopolyhydrophenanthrene compound with the mineral acid or strong alkali is a suitable solvent medium. We have found that lower aliphatic alcohols (inter alia methyl alcohol, ethyl alcohol, isopropyl alcohol) or water-lower aliphatic alcohol mixtures, are particularly suitable as reaction mediums for our process. j l

In practice, we find that although the temperature can be varied somewhat depending upon the particular compound being isomerized, generally maximum yields are achieved'by'tcarrying out the reaction of the A -IZ-keto compound with a strong alkali or a mineral'acidat room temperatures. I 1 The process of our invention isiparticularly valuable for converting 'A ,-12-ketocho1enic acids to the corresponding A -l2-ketocholenic acids. Thus,v we have found it to-be most useful for preparing 3-hydrpxy l 5 !-12-ketocholenic acid and esters thereof from the corresponding 3-hydroxynot having a 3-hydroxy subs-tituent. These par ticular reactions may be illustrated as follows:

wnereinn represents acarboxy group or an esteri'fied carboxygroup convertible to carboxy by hyyzljr'olysisv and R1 represents a hydroxy or an aoylo'xy substituent convertible to hydroxy by hydr'olysis. V V

,In carrying out the isomerization of a 3-hydroxy-A -12-ketocholenic acid to obtain the isomerized product having a double bond in the 9,11 position, we prefer to use a lower alkyl ester ofth fAW-compoundas: the starting material. Iii-effecting the reaction with this starting inaterialunder our preferred conditions, the startifiQ. Compound is-dissolved in a lower aliphatic alohoh'the mineral acid or strong alkali added thereto, and the resulting reaction mixturepermitted to stand at roomtemperature until the isomerization is completed. this case, the cciursaofI-the. reaction gi; e. theshii-ti-I 1g1;Dfthe double bondifrom the. 8,9 to the 9, 11- position is conveniently followed {by measuring the ultrav-iolet absorptionspectrum of the solution. Since the (A 4 compounds produced exhibit a c'haracteristic. absorption; spectrum due to the presence of ;a. conjugated doublefbondsystem; with chroniophoric' properties, .whreas the starting compounds do not have anQuItra-yiOlet absorption spectrum, the course of the reaction is .readily and. conveniently followed by measuring the absorption spectrum. Generally, we find that it is preferable when utilizing chol'enic acids or derivatiyes thereof as. the starting material .in our process; -not to -.per'rnitfthe reaction mixture to stand longer thand'fl hours-since. some decompos '-i}tion'. of the product appears to take placeafter v It isindeedjsurprji sihg to .fin'd that isomerization of A -12-keto c'yclopentanopolyhydrophenanthrenecompounds..can be effected to; yield the cor espondin A?' mp u d .Whi i' hi ingof double bond ing'steroids under'hydrogenatiOhj coneitionspr with hydrochloric, acid; and acetic jjacid has been g reported the .apocholic 'a 'cid series, -the1.50.1 9jrizati on or s steroids had not beenreported'previously. In the fapocholic acid series, the migrationof 7,8 r,1 4:,15' double bonds to the more stable 8,14 position'occurs'. and it is therefore, indeed unexpected tofind that the &-dou ble ,bond will shift to the 9,1'1-po'sition. The pr paratimiqf th st n ma ial. 3- a'ceto'xy A l2 -ketocholenic acid and'the methyl 4 ester thereof from cholic acid are described in the Journal of the Japanese Biochemical Society, volume 20, pages 144-447 (1948). The 3-hydroxy- A -12-ketocholenic acid is readily obtained by hydrolyzing the corresponding 3-acetoxy compound in accordance with methods known in the art.

The following examples are presented to illustrate specific embodiments of our invention:

Example 1 2 g. of 3(a) acetoxy-A 12-ketocholenic acid was dissolved-under nitrogen in 30 cc. of 0.6 N methanolic hydrogen chloride. The resulting solution quickly became pale yellow and all of the solid dissolved in one-half hour. The solution was then maintained at room temperature for forty hours and finally concentrated to dryness in vacuo. Water was added to the resulting residue; and the ofi-white solid was removed by filtration, washed with an aqueous sodium -bicarbonate solution, then {withwater, and finally dried; After recrystallization from aqueous methanol the methyl 391) hydroxy A9711 12- ke tocholenate was foundqto melt at 115-1l8 C. and did not -depress the melting point of authentic methyl- 3(a) -'hydroxy --A -12-ketocholenate. The product wasfound to have a specific rotation: [a]' '=+104 (1% in chloroform).- .p i i H The crude methyl-3 (a) -hydroxy-A 12-ketocholenate prepared above-was dissolved in .15 cc. of methanol and stirred. while 0.38 g. of sodium hydroxide in 1 cc. of water was added dropwise. The alkali was washed in with 1 cc. of water, and the solution was ilwarmed at 4042"" for 45 minutes. The yellow solution was diluted with 15 cc. of water and concentrated to amush in vacuo. Water (15 cc.) a'nd acetone (6" cc.) were added to the residue, and the solution was cooled to room temperature. The's'o'lution was stirred and-acidified to litmus with 1.1 cc. of glacial acetic acid added dropwise. Themixture was. diluted with ip; ccfof;water andfchilled for one hour. The solid was filtered, washed with waterand recrystallized twice from aqueous methanol. The 3 (a) -hydroxy n 12 ketocho1enic acid .sjo. obtained was if ound to melt at ,17 3475 C1 and had aspecific rotation of [a'l '+103 (1%. in chloroform). The product had an ultra-violet absofrptio'n."spectriun, A imaiximum 240011 1.; IE% g7.,.Ei 11,200.; material did" notIdepress the. melting point of an .allfilie litid sample P.

acid.

Example 2 1 g. of 3-acet0xy-A -12-ketocholenic acid was suspended in 20 cc. of methanol and 20 cc. of 30% sodium hydroxide was added. The reaction mixture was cooled to room temperature and kept standingjovernight. The dark green solution was concentrated to a slush in vacuo. The residue was dissolved in. hot water and acidified to litmus with 36% acetic acid. The acidified mixture was cooled,'filtered, and the precipitated 3(a) hydroxy A 12 ketocholenic acid was washed with water. The A -acid so obtained was-recrystallized from aqueous methanol, The 0 .7g.of product so obtained was found "to melt at 174-177" C. and a 1% chloroform solution had a rotation, [q] The ultra-violet absorption spectrum ,exhib'ite'da maximum, LA? at 2400513.; with E% "M 280. A'mix'ed melting point 0.335 g. of 3-hydroxy-A 12-ketocholenic acid was dissolved in 5 cc. methanolic HCl (0.6 molar HCl), and the solution was allowed to stand at room temperature. Formation of the A compound was recognized by measurement of the ultra-violet absorption spectrum; after 13 hours, A max. 2400 A. 12% 213.

Example 5 0.0168 g. of 3-hydroxy-A -12-ketocho1enic acid was dissolved in 1 cc. of methanolic sodium hydroxide (2.5 cc. methanol+2.5 cc. 30% aqueous NaOH). The solution was allowed to stand at room temperature, and the formation of the 3-hydroxy-A -12-ketocholenic acid was determined by measurement of the ultra-violet absorption spectrum of the solution:

After 13 hours, A max. 2400 A.-E% 171 After hours, A max. 2400 5. 200 After 37 hours, A, max. 2400 A. E% 279 Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. The process forpreparing a A -12-keto compound of the cyclopentanopolyhydrophenanthrene series which comprises reacting a A 12 keto cyclopentanopolyhydrophenanthrene compound with a member selected from the group consisting of mineral acids and strong alkalis.

2. The process for preparing a A -12-keto compound of the cyclopentanopolyhydrophenanthrene series which comprises reacting a A 9- 12 keto cyclopentanopolyhydrophenanthrene compound with a member selected from the group consisting of mineral acids and strong alkalis, and, recovering the corresponding A 12 keto cyclopentanopolyhydrophenanthrene compound from the resutling reaction mixture.

3. The process for preparing a A -I2-ketocompound of the cyclopentanopolyhydrophenanthrene series which comprises reacting a A 12 keto cyclopentanopolyhydrophenanthrene compound with a mineral acid.

4. The process for preparing a A -12-keto compound of the cyclopentanopolyhydrophenanthrene series which comprises reacting a A 12 keto cyclopentanopolyhydrophenanthrene compound with a strong alkali.

' 5. The process for preparing a A -12-ketocholenic acid which comprises reacting 2. A

1 -ketocholenic acid with a mineral acid.

6. The process for preparing a A -12-ketocholenic acid which comprises reacting a A- 12-ketocholenic acid with a strong alkali.

6 7. The process for preparinga'coinp'ound of the formula:

wherein R is a member selected from the group consisting of carboxy and esterified carboxy which comprises reacting a mineral acid with a; compound of the formula:

wherein R is a member selected from the group consisting of carboxy and esterified carbon and R1 is a member selected from the group consisting of hydroxy and acyloxy.

8. The process for preparing a compound of the formula:

which comprises reacting a strong alkali with a compound of the formula:

wherein R is a member selected from the group consisting of carboxy and esterified car-boxy and R1 is a member selected from the group consisting of hydroxy and acyloxy.

9. The process for preparing 3-hydroxy-A 12-ketocholenic acid which comprises reacting 3-hydroXy-A -12-ketocholenic acid with a mineral acid.

10. The process for preparing 3-hydr0xy-A 12-ketocholenic acid which comprises reacting 3-hydroxy-A -12-ketocholenic acid with a stron 1 alkali.

11. The process for preparing a lower alkyl ester of 3-hydroxy-A -ketocholenic acid which comprises reacting a lower alkyl ester of 3-hydroxy-A -l2-ketocholenic acid with a mineral acid.

12. The process for preparing 3-hydroxy-A 7 ketocholenic acid which comprises reacting a lower alkyl ester of 3-hydroxy-A r2 ketocholenic acid with a strong alkali.

13. The process for preparing a lower alkyl I ester of 3-hydroxy-A -12-ketocholenic acid which comprises reacting a lower alkyl ester of 3-acy1oxy-A -12-keto'cho1enic acid with a mineral acid.

14. The process -for preparing 3-hydroxy-A 12-ketocholenic acid which comprises reacting a lower alkyl ester of 3-acy1oxy-A -12-ketocholenic acid with a strong alkali.

15. The process for preparing methyl 3(a) -hydrojxy-N" --1 2 =ketocho1ena-te which comprises reacting "methyl 3(a) '--hydroxy-A %12=ketdcholeneitei with a mineral acid.

I6. The process for preparing. 3(*a) -hydr0Xy- A -IZQketochQIenic' acid'which. comprises reacting methyl 3(a) hydroxy-A -12-ketoch0- lenate with a strong alkali. 17'. The process for preparing methyl 3.(n)-hy droXy-M- 12=ketocho1enate which comprises reactingv methyl 3(a) "-acetoxy lmketocholenate with afmineral acid- '18. The process for preparing: 3(w)-hydroxy- A 1-2'-ketocho1enic acid which comprises reacting methyl 3(a)- acetoxy-12-ketocholenate with a strong alkali.

EVELYN H. WILSON. MAX TISHLER.

'Noreferences cited. 

1. THE PROCESS FOR PREPARING A $9.11-12-KETO COMPOUND OF THE CYCLOPENTANOPOLYHYDROPHENANTHRENE SERIES WHICH COMPRISES REACTING A $8,912 - KETO CYCLOPENTANOPOLYHYDROPHENANTHRENE COMPOUND WITH A MEMBER SELECTED FROM THE GROUP CONSISTING OF MINERAL ACIDS AND STRONG ALKALIS. 